CLINICAL THERAPEUTICS’VVOL. 23, NO.

7,200l

New Drugs

Tenecteplase: A Review

Liya Davydov, PharmD,l and Judy WM. Cheng, PharmD, BCPS1p2

‘Mount Sinai Medical Center; New York, and 2Amold & Marie Schwartz College of
Pharmacy and Health Sciences, Long Island University, Brooklyn, New York

ABSTRACT

Background: Certain shortcomings of the available thrombolytic agents have prompted

the search for a more fibrin specific fibrinolytic agent with a longer half-life. Such properties
would allow bolus administration, possibly leading to faster reperfusion of occluded arteries.
Objective: This article focuses on the new thrombolytic agent tenecteplase, reviewing
its mechanism of action, pharmacokinetic characteristics, clinical efficacy, tolerability,
and potential for drug interactions in the management of acute myocardial infarction.
Methods: English-language articles for inclusion in this review were identified through
searches of MEDLINE@, EMBASE@, and International Pharmaceutical Abstracts from
1966 to April 2001. The search terms used included tenecteplase, myocardial infarction,
TNK, and TNK-tPA. Abstracts from recent conferences and symposia were also consulted.
Results: Tenecteplase is a variant of the native tissue-type plasminogen activator (tPA)
molecule that has 16fold greater fibrin specificity than alteplase, a longer half-life, slower
plasma clearance, and 80-fold greater resistance to inhibition by plasminogen activator in-
hibitor type 1. Its half-life of -18 minutes allows single-bolus administration. In compar-
ative clinical trials, tenecteplase was found to have equivalent efficacy to recombinant tPA
(alteplase). The rate of intracranial hemorrhage with tenecteplase was similar to that with
alteplase, and tenecteplase was associated with fewer noncerebral complications and less
need for blood transfusions.
Conclusions: Tenecteplase appears to be as effective and well tolerated as alteplase in
the management of acute myocardial infarction and offers the convenience of single-
bolus administration.
Key words: tenecteplase, thrombolytic, acute myocardial infarction, clinical pharma-
cology. (Clin Thel: 2001;23:982-997)

Accepted for publication May 10, 2001.

Printed in the USA. Reproduction in whole or part is not permitted.

982 0149.2918/01/$19.00
L. DAVYDOV AND J.W.M. CHENG

INTRODUCTION involving bolus injection followed by a 2-

step 90-minute infusion. The time to de-
The treatment of acute myocardial infarc- livery of therapy and risk of medication
tion (AMI) has undergone substantial errors are increased by this complicated
changes since the early 1970s when pa- front-loaded dosing regimen and the need
tients were managed with heparin, aspirin, for 2 IV access sites (for alteplase and
and bed rest. The advent of thrombolytic heparin). ‘9’ The second-generation fibri-
agents led to a significant decrease in the nolytic agent reteplase can be given as 2
mortality of AMI.’ Four thrombolytic IV boluses administered 30 minutes
agents are currently indicated for the treat- apart.* Bleeding complications are also a
ment of AM1 in the United States (in or- risk with thrombolytic agents, which are
der of their introduction, streptokinase, associated with a 0.5% to 0.9% incidence
alteplase, reteplase, and tenecteplase). of intracranial hemorrhage. 1+1 1
Alteplase was demonstrated to be more Newer thrombolytic agents such as
effective then streptokinase in the tenecteplase have been developed with
GUSTO (Global Use of Strategies to a focus on longer half-life, higher fi-
Open Occluded Coronary Arteries) I brin specificity, and greater resistance to
study2 and has since become the standard plasminogen activator inhibitor type 1
against which new thrombolytic agents (PAI-l).* A longer half-life would allow
are compared. single-bolus administration, which would
Based on published data on reper- result in rapid delivery of large concen-
fusion rates and mortality, the updated trations of fibrinolytic therapy, theoreti-
1999 American College of Cardiology/ cally increasing the reperfusion rate.
American Heart Association guidelines’ Higher fibrin specificity could increase
recommend the use of accelerated (front- potency and time to patency, and decrease
loaded) dosing of alteplase and reteplase. the incidence of bleeding events. In addi-
However, both agents are more expen- tion, higher resistance to PAI- has the
sive than streptokinase and are associated potential for increased potency, particu-
with a greater risk of intracranial hemor- larly with respect to the lysis of platelet-
rhage. The cost-benefit ratio of these rich clots.8,12
agents is greatest in patients presenting This article focuses on the mechanism
<6 hours after the onset of chest pain3p4 of action, pharmacokinetic characteristics,
patients with large (anterior) infarctions, clinical efficacy, tolerability, and potential
and patients at low risk of intracranial for drug interactions of tenecteplase, and
hemorrhage.’ reviews current research on the use of this
Nonetheless, the currently available agent in the management of AMI. Clini-
thrombolytic agents have several short- cal studies were identified by searches of
comings. Despite their efficacy, they fail MEDLINE@, EMBASE@, and Interna-
to restore perfusion in as many as 50% tional Pharmaceutical Abstracts from
of patients and fail to prevent reocclusion 1966 to April 2001 using the search terms
in another 20%.5 In addition, the short tenecteplase, myocardial infarction, TNK,
half-life of first-generation thrombolytics and TNK-tPA. Supplemental information
such as alteplase6 requires that they be was obtained from abstracts presented at
administered in a complicated regimen recent conferences and symposia.

983
 CLINICAL THERAPEUTICS’

TENECTEPLASE greater specificity, and tenecteplase has

the greatest specificity.16 With its high fi-
Tenecteplase is a variant of native tissue- brin specificity, tenecteplase binds with a
type plasminogen activator (tPA) that has greater afIinity to the fibrin-rich clot and,
been produced by recombinant DNA tech- to a much lesser extent, to the circulating
nology, having undergone multiple-point plasminogen.12~‘6
mutations.13 It is a glycoprotein compris- Although fibrin stimulates tenecteplase
ing 527 amino acids. I4 The substitution of and alteplase to a similar degree, resulting
asparagine 103 for threonine 103 created in comparable fibrinolytic activity, less
a new glycosylation site, which both en- fibrinogenolysis has been observed with
larged the molecule and prolonged its tenecteplase than with alteplase, as (DD)E
half-life.t5 The substitution of glutamine (a complex of D-dimer noncovalently
117 for asparagine 117 resulted in reduced linked to fragment E, a major degradation
clearance, eliminating the high mannose- product of cross-linked fibrin) stimulates
type side chain and contributing to the ex- tenecteplase to a lesser degree than it does
tended half-life of the molecule.t5 Finally, alteplase.
replacement of the lysine 296-histidine A recent study of factors involved in
297-arginine 29%arginine 299 sequence the higher fibrin specificity of tenecteplase
within the protease domain with 4 alanine compared with alteplase demonstrated
residues increased resistance to PAI- 1.15 that T-mutation in tenecteplase leads to a
Thus, tenecteplase has a longer half-life reduction in lysine binding and thus a
than alteplase (- 18 minutes vs -4 minutes, decreased affinity for (DD)E.17 The K-
respectively), higher fibrin specificity (14- mutation in tenecteplase, on the other
fold), and increased resistance to PAI- hand, is responsible for decreased plas-
(80-fold).15 min formation in the presence of (DD)E.
Tenecteplase is currently indicated only The combined effects of these mutations
for the treatment of AMI. It is recom- produce a reduction in the catalytic effi-
mended that the drug be started as soon as ciency of plasminogen activation when
possible within 12 hours after the onset of (DD)E is present, explaining the higher
symptoms.14 Alteplase is the only fibri- fibrin specificity of tenecteplase compared
nolytic agent currently approved in the with alteplase.
United States for use in ischemic stroke
and pulmonary embolism as well as in
PHARMACORINETIC AND
AMI.
PHARMACODYNAMIC PROFILES

Early animal data demonstrated that the

MECHANISM OF ACTION
area under the concentration-time curve
All thrombolytic agents promote conver- for tenecteplase was 8.4-fold greater than
sion of plasminogen to plasmin after the that for alteplase, resulting in clearances
occurrence of thrombosis, leading to clot of 1.9 and 16.1 mL/min per kg for
dissolution and restoration of coronary tenecteplase and alteplase, respectively.i2
perfusion.i6 Of the available thrombolytic This translates into an -8-fold slower
agents, streptokinase is the least fibrin clearance of tenecteplase than alteplase.12
specific; reteplase and alteplase have Slower clearance from plasma and longer

984
L. DAVYDOV AND J.W.M. CHENG

initial half-life (-9 vs 1.3 minutes for to 138 _+ 84 minutes. There was a signifi-
tenecteplase and alteplase, respectively, in cant decrease in clearance with increasing
the o~ phase of elimination) lead to an dose (P < 0.001). The clearance was also
increased systemic residence time for found to be longer in women (however,
tenecteplase, allowing its administration only 10 women were included; P = NS)
as a bolus dose. Keyt et a112 demonstrated and patients aged >65 years (P = 0.023).
differences in the early phases of clearance The regression model also demonstrated
of tenecteplase and alteplase, with 50% of a negative correlation between clearance
tenecteplase and 1% of alteplase remaining and body weight (P = 0.009 for total body
in the circulation 15 minutes after injection, weight; P = 0.001 for lean body weight).
whereas the terminal phases of these agents Another study in human subjects (a sub-
were equivalent 2 hours after injection. study of the TIMI 10B 22 trial) compared
Although 1 animal study 18 found that the pharmacokinetics of boluses of ten-
tenecteplase clearance followed a mono- ecteplase 30, 40, and 50 mg in 96 pa-
phasic elimination profile in rabbits, this tients (69 men, 27 women) with those of
has not been confirmed by other animal an accelerated regimen of <100 mg al-
studies or studies in human subjects. In teplase in 53 patients (38 men, 15 wom-
fact, Keyt et al ~2 found that clearance en). 23 Tenecteplase was cleared in a bipha-
of tenecteplase in rabbits followed a bi- sic pattern, with a mean plasma clearance
phasic pattern, with calculated initial- and of 105 mL/min across all doses, compared
terminal-phase half-lives of - 9 and 31 with a clearance of 453 mL/min for al-
minutes, respectively. teplase. Sixty-six percent to 75% of the
The results of pharmacokinetic studies total area under the curve for tenecteplase
in human subjects 19,a° indicate that 50-mg was attributed to the initial phase. The ini-
boluses of both tenecteplase and alteplase tial half-life of tenecteplase was 22 min-
produce similar initial concentrations (9.1 utes and the terminal half-life was 115
and 9.8 p~g/mL, respectively). Modi et a119 minutes, whereas alteplase had a terminal
administered tenecteplase 5 to 50 mg to half-life of 144 minutes. The initial vol-
78 patients (a substudy of the TIMI ume of distribution of tenecteplase was
[Thrombolysis in Myocardial Infarction] -4.7 L, similar to the plasma volume (and
10A zl trial) and found a dose-dependent to the findings of Modi et a119). The
increase in tenecteplase plasma concen- steady-state volume of distribution was
trations. Mean tenecteplase clearance was calculated to be 45% greater (6.1 L), lead-
dose dependent and ranged from 216 ing to the assumption that tenecteplase
mL/min for the 5-mg dose to 125 mL/min distributes into extravascular compart-
for the 50-mg dose. The mean (___SD) ini- ments as well. In comparison, both the
tial volume of distribution (4.3 _+ 2 L to initial and steady-state volumes of distri-
8.4 _+ 6 L) was found to be similar to the bution of alteplase (7.2 and 28.9 L, re-
plasma volume, with the steady-state vol- spectively) were greater than those of ten-
ume of distribution in the range from 6.3 _+ ecteplase. Unlike Modi et al, this study
2 L to 15 _+ 7 L. Depending on the dose, failed to find a decrease in tenecteplase
the initial half-life ranged from 11 _ 5 plasma clearance with increasing dose,
minutes to 20 _+ 6 minutes, and the termi- but this may be attributed to the narrower
nal half-life ranged from 41 _+ 16 minutes dose range studied (30-50 mg in this study

985
 CLINICAL THERAPEUTICS”

vs 5-50mg in Modi et al). It did find, compared with currently used throm-
however, that each lo-kg increase in body bolytic agents. In a study in rabbits fitted
weight led to a 9.6-mL/min increase in with an extracorporeal arterial venous
plasma clearance of tenecteplase, whereas shunt containing whole blood clots, Keyt
each lo-year increase in age led to a 16. l- et alI2 found that the initial rates of lysis
mL/min decrease in plasma clearance. with equipotent doses of tenecteplase ad-
No sex differences were noted, although ministered as a bolus and alteplase admin-
men generally had a 19.2~mL/min faster istered as an infusion were 1.5% and 0.5%,
plasma clearance than women. respectively. These authors reported that it
Tenecteplase is metabolized in the liver, took nearly 3 times longer for alteplase to
and metabolites are excreted in the achieve 50% lysis than it did tenecteplase
urine.14~16 It has been speculated that the (120 vs 35 minutes, respectively).
decrease in plasma clearance with in- Benedict et all8 compared the throm-
creasing doses of tenecteplase may be due bolytic properties of tenecteplase and al-
to saturation of hepatic enzymes respon- teplase in a rabbit thrombosed carotid
sible for the clearance of the drug.19 Con- artery model. At equipotent doses of
comitant administration of nitrates and tenecteplase 1.5 mg/kg administered as a
beta-blockers does not seem to affect the bolus and alteplase 9 mg/kg administered
pharmacokinetics of tenecteplasei9 as it as an infusion (the highest tested doses of
does those of alteplase.24 both), the mean (+ SD) duration of re-
In a study in rabbits,12 the fibrinolytic canalization was significantly longer with
activity of tenecteplase on a plasma-based tenecteplase than with alteplase (77 + 9
clot has been reported to be -81% that of vs 5 1 f 18 minutes; P < 0.025), and the
alteplase. However, in the same study, mean (k SD) time to reperfusion was sig-
tenecteplase was S-fold more potent than nificantly shorter (11 + 2 vs 23 f 7 min-
alteplase in lysing whole blood clots. As utes; P < 0.02). These authors concluded
mentioned earlier, tenecteplase is a tPA that given as a bolus, tenecteplase pro-
mutant with a high resistance to PAI- 1.I5 duced more rapid and complete recanal-
Keyt et all2 found that the mutation at the ization of occluded arteries in rabbit mod-
K-site was responsible for an SO-fold in- els than did alteplase.
crease in resistance to PAI- compared Collen et a126 compared the throm-
with alteplase. These authors hypothe- bolytic potency of tenecteplase and al-
sized that the increase in PAI- resistance teplase administered as IV infusions over
is responsible for tenecteplase’s 13.5fold 60 minutes in a combined venous and ar-
greater potency in lysing platelet-rich terial thrombosis model in dogs. The
clots in vivo compared with alteplase. thrombolytic potency of tenecteplase (ex-
pressed as the rate of clot lysis/dose in
mg/kg) was found to be 3-fold greater
EFFICACY
than that of alteplase (P= 0.004). Theau-
In Vitro and Animal Data thors reported that tenecteplase (at the
lowest tested dose, 0.125 mg/kg) had
In early in vitro and animal stud- greater efficacy than alteplase, which was
ies 12~18,25-28
tenecteplase demonstrated an consistent with the findings of other ani-
improved thrombolytic profile and potency mal studies.29

986
L. DAVYDOV AND J.W.M. CHENG

Thomas et a128 compared the throm- The first study of the pharmacokinet-
bolytic potency of tenecteplase and al- its, efficacy, and tolerability of tenec-
teplase in rabbit models of embolic stroke teplase in patients with AM1 was the TIM1
and peripheral bleeding. Bquipotent doses 10A trial.*l This was a multicenter, open-
of tenecteplase and alteplase were admin- label, dose-ranging angiographic study
istered as a bolus and an IV infusion, re- that included 113 patients (84% male,
spectively. Dose-dependent clot lysis was 16% female) who presented within 12
observed. On a mg/kg basis, tenecteplase hours of the onset of AM1 with ST-
was -20 times more potent than alteplase, segment elevation and who had no con-
and based on these findings, the investi- traindications to thrombolytic therapy. Pa-
gators concluded that tenecteplase may be tients were given 8 sequential doses of
more potent (allowing use of lower doses) tenecteplase in the following order: 5,7.5,
than alteplase, and more convenient to ad- 10, 15, 20, 30, 40, and 50 mg. All doses
minister (bolus vs IV infusion). were administered as a single bolus over
There are discrepancies between the re- 5 to 10 seconds. Concomitant medications
sults of the in vitro studies. Some indicate included IV heparin infusion and IV or
that due to its slower plasma clearance, oral aspirin daily; beta-blockers were ad-
longer half-life, and increased potency, ministered as appropriate. Other medica-
especially in lysing compacted plasma tions were administered at the discretion
clots and platelet-rich clots, tenecteplase of the investigators. Clinical end points
may offer significant advantages over included the rate of TIM1 grade 3 flow
other thrombolytic agents.12,25,28 Others (defined as complete perfusion, graded on
report that tenecteplase was only slightly a scale from 0 = no perfusion to 3 = com-
better at lysing clots than alteplase3’ and plete perfusion)3’ at 60 to 90 minutes,
that increased fibrin specificity may not TIMI frame count (defined as the number
necessarily produce a dramatic increase of cineframes required for contrast mate-
in the rate of clinical reopening of oc- rial to first reach standard distal coronary
cluded arteries, as tenecteplase was not landmarks),32 and the incidence of serious
significantly better than alteplase in terms bleeding, anaphylaxis, and systemic de-
of maximal speed of clot lysing.25 The re- pletion of coagulation factors.
sults of animal studies, on the other hand, The investigators found that the achieve-
suggest that tenecteplase has greater po- ment of TIM1 grade 3 flow in the infarct-
tency than alteplase in lysing clots and related artery at 90 minutes appeared to be
producing more rapid recanalization of greater at tenecteplase doses of 30 to 50 mg
occluded arteries.12~‘8~26~28 than at lower doses (P = 0.032) (Table I).*l
Sixty minutes after bolus administration
of tenecteplase, TIM1 grade 3 flow was
Human Studies and Comparative TriQb
achieved in a substantial number of pa-
Based on the data obtained from in vitro tients who received 30- and 50-mg doses
and animal studies, studies in humans have (39% and 43%, respectively) (Table I). Ob-
been designed to test whether the increased jective assessment of coronary blood flow
thrombolytic potency of tenecteplase on the basis of TIM1 frame count found
translates into increased clinical efficacy that 62% and 68% of patients receiving the
compared with other thrombolytic agents. 30- and 50-mg doses, respectively, had a

987
 CLINICAL THERAPEUTICS”

whether maintaining patency of coronary

Table I. Correlation between doses of arteries translated directly into mortality
tenecteplase and percentage of and morbidity benefits could not be de-
patients achieving TIM1 grade 3 termined from the findings of this study.
flow at 60 and 90 minutes.21 Based on the results of the TIM1 10A
trial,21 which indicated the feasibility of
% of Patients with bolus administration and the preliminary
TIM1 Grade 3 Flow
efficacy and tolerability of 30- to 50-mg
Dose, At At doses, the TIM1 10B22 trial was designed
mg 60 Minutes 90 Minutes to prospectively compare tenecteplase 30,
40, and 50 mg and front-loaded alteplase
5 NA 0 in terms of angiographic efficacy and tol-
7.5 NA 60 erability to identify the appropriate dose
10 NA 40 of tenecteplase for testing in a large-scale
15 NA 17 mortality trial. TIM1 10B was a multicen-
20 NA 29 ter, dose-ranging, randomized, open-label
30 39 59*
trial enrolling 837 patients with ischemic
40 NA 57*
pain lasting for 230 minutes (but <12
50 43 64*
hours) associated with ST-segment eleva-
TIM1 = Thrombolysis in Myocardial Infarction; tion 20.1 mV in 22 contiguous leads.
NA = not available. Early in the study, the 50-mg dose was re-
‘P = 0.032 versus doses ~30 mg. placed by 40 mg because of a higher in-
cidence of intracranial hemorrhage asso-
TIM1 frame count of <40 frames at 90 min- ciated with its use (3.8% in 50-mg group,
utes, equivalent to having TIM1 grade 3 1.9% in the 40-mg group, 1.0% in the 30-
flow. Also, 45% of patients receiving 30 mg group; no statistical analysis was per-
to 50 mg had a TIM1 frame count of 127 formed). Three hundred two patients re-
frames, corresponding to normal coronary ceived tenecteplase 30 mg, 148 received
flow in persons without AMI. Although 40 mg, and 76 received 50 mg; 3 11 re-
this study was not designed to assess mor- ceived alteplase. Concomitant aspirin and
tality rate, mortality at 30 days was 3.5%. heparin were administered; however, it
The TIM1 10A2’ investigators indicated was noted early in the trial that patients
that tenecteplase’s longer half-life com- experienced higher rates of intracranial
pared with alteplase allowed its adminis- hemorrhage with higher heparin doses
tration as a bolus, and that the initial pat- (go-U/kg bolus and 18-U/kg/h infusion)
ency results and the proportion of patients versus lower heparin doses (2.2% vs O%,
with an optimal TIM1 frame count of ~40 respectively, in the tenecteplase groups,
(60%-68% with tenecteplase in TIM1 10A and 2.8% vs 1.2%, respectively, in the al-
vs 53% with front-loaded alteplase in teplase group; overall combined P = 0.04).
TIM1 433) were encouraging. However, As a result, the protocol was altered to
because this was not a direct comparative mandate administration of heparin as a
trial against alteplase, it was not possible 5000-U bolus and 1000-U/h infusion in
to draw any conclusions concerning clin- patients weighing >67 kg, and as a 4000-
ical equality or superiority. In addition, U bolus and 800-U/h infusion in patients

988
L. DAVYDOV AND J.W.M. CHENG

weighing 167 kg, adjusted as necessary to patients who received heparin before and
achieve the desired target activated partial after amendment of the protocol. There
thromboplastin time of 55 to 80 seconds. were no significant differences between
Also, an upper age limit of 80 years and the 2 agents in the rate of restoration of
abciximab use in the first 96 hours of ran- normal coronary flow, defined as TIM1
domization were added to the exclusion frame count 127 frames. When a weight-
criteria. The primary efficacy end point based dosing analysis was performed, pa-
was the rate of TIM1 grade 3 flow at 90 tients who received 0.5 mg/kg of tenec-
minutes. The study also assessed TIM1 teplase had a TIM1 grade 3 flow of 62%
grade 3 flow at 60 and 75 minutes, TIM1 to 63%, whereas those who received doses
grade 2 or 3 flow and TIM1 frame count at co.5 mg/kg had a TIM1 grade 3 flow of
all time points, and other clinical end 5 1% to 54% (P= 0.028). Also, in patients
points including recurrent MI and systemic receiving a higher weight-based dose,
depletion of coagulation factors.3“-36 faster restoration of coronary flow was
Compared with alteplase, the 40-mg observed, as demonstrated by a signifi-
dose of tenecteplase produced a similar cantly lower median TIM1 frame count
TIM1 grade 3 flow at 90 minutes (62.7% (3 1 for those receiving a dose in the high-
and 62.8%; P = NS)(Table II).22 Rates of est tertile vs 35 for those receiving a dose
achievement of TIM1 grade 2 or 3 flow in the middle tertile, P = 0.05; 3 1 for those
increased with increasing doses (76.8%, receiving a dose in the highest tertile vs
79.1%, and 88.2% for the 30-, 40-, and 38 for those receiving a dose in the low-
50-mg doses of tenecteplase, respectively, est tertile, P = 0.001). Although the study
vs 8 1.7% for alteplase; P = 0.044). There was not designed to assess mortality, the
were no differences in TIM1 flow grade in overall mortality rate at 30 days was 4.9%,
and no significant difference was observed
between the 2 agents. The authors con-
Table II. Correlation between doses of cluded that weight adjustment was impor-
tenecteplase and alteplase and tant in achieving maximum reperfusion.
percentage of patients achieving Based on the efficacy results of this trial
TIMIgrade3flowat6Oand90 and the safety results of the ASSENT-l
minut&.22 (Assessment of the Safety and Efficacy
of a New Thrombolytic) tria1,37 it was
% of Patients with recommended that a “stepped” weight-
TIM1 Grade 3 Flow
adjusted tenecteplase dose of 0.5 mg/kg
At At be used in the phase III trial.
60 Minutes 90 Minutes The phase III ASSENT-2 study38 is the
only large comparative mortality trial to
Tenecteplase date involving the use of tenecteplase. It
30 mg 48.9 54.3’ was a multicenter (1021 hospitals), inter-
40 mg 54.5 62.8
national, randomized, double-blind, con-
50 mg 45.2 65.8
trolled comparison of the efficacy and tol-
Alteplase 48.2 62.7
erability of tenecteplase with those of
TIM1 = Tbrombolysis in Myocardial Infarction. alteplase, designed to examine the hy-
‘P = 0.035 versus alteplase. pothesis of therapeutic equivalence be-

989
 CLINICAL THERAPEUTICS”

tween single-bolus tenecteplase and front- to inhibition by PAI-1, and thus may cause
loaded alteplase, as determined by all- less activation of systemic plasminogen
cause mortality at 30 days. A total of 16,949 compared with currently used thrombolytic
patients were randomized to receive ten- agents such as alteplase and reteplase, re-
ecteplase and alteplase placebo (n = 8461; sulting in a reduced incidence of bleeding
77.1% male, 22.9% female) or alteplase events. Benedict et al’s demonstrated that
and tenecteplase placebo (n = 8488; 76.7% both tenecteplase and alteplase decreased
male, 23.3% female). Tenecteplase was plasma levels of %-antiplasmin, functional
administered according to body weight as plasminogen, and rapidly clottable fibrino-
follows: ~60 kg, 30 mg; 60 to 69.9 kg, 35 gen in a dose- and time-dependent manner
mg; 70 to 79.9 kg, 40 mg; 80 to 89.9 kg, in rabbits. Although the reductions in plas-
45 mg; and 290 kg, 50 mg. Front-loaded minogen, fibrinogen, and a,-antiplasmin
alteplase was given as a 15mg bolus, fol- were significantly increased with increas-
lowed by infusions of 0.75 mg/kg over the ing doses of alteplase (P < [Link]), reduc-
first 30 minutes and 0.5 mg/kg over the tions in these parameters were only mod-
next 60 minutes. Patients received weight- erate with increasing doses of tenecteplase.
based heparin according to the protocol There was also a significant increase
used in TIM1 lOB.** The primary efficacy in blood loss from the incision site in
end point of ASSENT-2 was all-cause mor- alteplase-treated animals compared with
tality at 30 days. tenecteplase-treated animals (160 vs 118
There was no significant difference in mg mean blood loss, respectively; P <
total 30-day mortality between tenecte- 0.02). Finally, whereas low and moderate
plase and alteplase (6.179% vs 6.151%, doses of alteplase tended to potentiate
respectively; RR 1; 95% CI, 0.89-l. 12).38 collagen-sensitized platelet aggregation, no
When univariate analyses were performed, doses of tenecteplase produced a similar
a lower rate of 30-day mortality was ob- effect (>50% platelet aggregation with al-
served among patients treated after 4 hours teplase vs ~10% with tenecteplase). The
from the onset of symptoms with tenecte- results of this study indicated that in rab-
plase compared with alteplase (7.0% vs bits, tenecteplase has the ability to produce
9.2%; P = 0.018). However, when mortal- sustained recanalization due to its lack of
ity data were adjusted for 5 covariates (age, effect on platelet aggregation and is asso-
Killip class, 39 heart rate, systolic blood ciated with decreased bleeding. It was not
pressure, and infarct location), the differ- possible to demonstrate, however, that the
ence in mortality between the 2 treatments lower incidence of bleeding was a direct
decreased to nonsignificance. The authors result of the increased fibrin specificity of
concluded that based on 30-day mortality, tenecteplase, and the investigators sug-
single-bolus tenecteplase and front-loaded gested that only a large comparative clini-
alteplase are of equivalent efficacy. cal trial in human subjects would be able
to determine whether there was a signifi-
cant decrease in bleeding with tenecteplase
SAFETY PROFILE
compared with alteplase.
Early in vi~ol*JO and ~~~ma~~*~~8~*62*~*9
TIM1 10A2* found that as in the animal
data showed that tenecteplase has increased data, tenecteplase had minimal effects on
fibrin specificity and increased resistance systemic coagulation, with mean de-

990
L. DAVYDOV AND J.W.M. CHENG

creases of 13% in plasminogen, 3% in fi- weight-based dose of tenecteplase (>0.55

brinogen, and up to 30% in c$antiplasmin mg/kg, 12.0% and 5.6%, respectively;
levels. These decreases were much smaller 0.484.55 mg/kg, 4.5% and 0%; 0.42-0.48
than the 50% to 60% decreases in both mg/kg, 0.9% and 0.9%; 0.35-0.42 mg/kg,
plasminogen and fibrinogen and 70% to 1.9% and 0.9%; ~0.035 mg/kg, 1.9% and
80% decreases in a,-antiplasmin that have 0.9%). New-onset pulmonary edema, car-
been reported with alteplase in several stud- diogenic shock, and reinfarction occurred
ies.4W2 The TIM1 10A trial also reported with similar frequency in the tenecteplase
that 4.4% of patients experienced reinfarc- and alteplase groups. Only 1 patient de-
tion, 2.7% had new-onset pulmonary veloped antibodies to tenecteplase at 30
edema, and 6.3% had serious bleeding, days; no antibodies were present in this
mostly from the vascular access site. No patient at 90 days. The authors concluded
strokes or intracranial hemorrhages were that the higher fibrin specificity of tenec-
reported, and no antibodies to tenecteplase teplase did not prevent intracranial hemor-
were detected in any patient at 30 days. rhage, nor did it lead to improved throm-
As stated earlier, although TIM1 10B22 bolytic efficacy compared with alteplase.
initially compared 30-, 40-, and 50-mg doses The ASSENT-l triak3’ which was car-
of tenecteplase with alteplase, early in the ried out simultaneously with TIM1 10B,22
trial the 50-mg dose was replaced by 40 mg was designed to determine the tolerability
and heparin dosing was amended because of several doses of tenecteplase adminis-
of the higher incidence of intracranial hem- tered as a bolus in human subjects. This
orrhage observed with 50 mg tenecteplase multicenter, international, prospective,
and higher doses of heparin. As in TIM1 randomized, uncontrolled trial enrolled
l0A,21 the decreases in fibrinogen, plas- 3235 patients who met the inclusion cri-
minogen, and a2-antiplasmin were much teria of TIM1 10A21 and TIM1 10B.22 On
smaller with tenecteplase than with al- randomization, 1705 patients received 30
teplase, but no statistical analysis was con- mg tenecteplase, 1457 received 40 mg,
ducted. In the early phase of the trial, and 73 received 50 mg. The 50-mg dose
before the reduction in heparin dosing, was discontinued soon after initiation of
the incidence of intracranial hemorrhage the trial as a result of the increased rate of
was 3.8% in patients receiving 50 mg intracranial hemorrhage reported with this
tenecteplase. The overall rates of intracra- dose in TIM1 10B. Overall, intracranial
nial hemorrhage were 1.O% with 30 mg ten- hemorrhage occurred in 0.77% of patients
ecteplase, 1.9% with 40 mg, and 3.8% with in ASSENT- 1. Death occurred in 6.4% of
50 mg, compared with 1.9% with alteplase. patients, death or nonfatal stroke in 7.4%,
Serious bleeding occurred in 1.9%, 5.2%, and severe bleeding complications in
and 11.5% of patients treated with 30, 2.9%. The authors stated that the safety
40, and 50 mg tenecteplase, respectively profile of tenecteplase at bolus doses of
(P < 0.001 across all 3 groups), compared 30 and 40 mg was comparable to that re-
with 8.5% of patients treated with alteplase ported for accelerated alteplase in other
(P < 0.001 tenecteplase groups vs alte- trials. However, because ASSENT-l was
plase). Significantly more serious bleeding not a direct comparative trial of tenecte-
(P = 0.001) and intracranial hemorrhage plase and alteplase, no definitive conclu-
(P = 0.033) were observed at the highest sions could be drawn. In addition, the

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 CLINICAL THERAPEUTICS@

study did not control how medications plase is given as a l-time dose, no such
such as heparin were used. As is now un- studies are anticipated. However, patients
derstood, the concurrent use of high-dose were routinely treated with aspirin and
heparin with thrombolytic agents can heparin in the clinical trials of tenec-
cause an increased risk of bleeding. teplase. Caution is advised when admin-
Results of the ASSENT-2 triaP8 showed istering tenecteplase concomitantly with
that whereas the rate of hemorrhagic stroke other drugs that may increase the risk of
was similar with tenecteplase and alteplase bleeding (eg, dipyridamole, clopidogrel,
at 30days (0.93% vsO.94%), significantly low-molecular-weight heparin, direct
fewer bleeding complications were ob- thrombin inhibitors, glycoprotein IIb/IIIa-
served in the tenecteplase group (26.43% receptor inhibitors), as additive effects
vs 28.95%; P < [Link]), leading to a sig- may occur. I4
nificantly lower need for blood transfu-
sion in the tenecteplase group (4.25% vs
RESEARCH IN PROGRESS
5.49%; P < 0.001). No significant differ-
ences were found in the rate of reinfarc- The hypothesis that combination therapy
tion, cardiogenic shock, or pulmonary em- with thrombolytic agents and glycoprotein
bolism between the 2 agents. The authors IIb/IIIa-receptor inhibitors may increase
suggested that the higher fibrin specificity efficacy is based on a new understanding
of tenecteplase might be responsible for of the thrombotic process in AMI. Whereas
fewer noncerebral complications and a the occlusive coronary thrombus was once
lower requirement for blood transfusions. thought to be composed primarily of fi-
Finally, a recent study43 addressed the brin and red blood cells (“red clot”), it is
overall tolerability of the 50-mg dose of now known that a significant portion of
tenecteplase in subsets of patients from the thrombus is composed of platelets
TIMI 10BF2 ASSENT-Ls7 and ASSBNT-238 (“white clot”). During an AMI, there is an
who had received this dose of tenecteplase increase in platelet activation and adhe-
(N = 1924). Thirty-day mortality with this sion that may lead directly or indirectly to
dose was 4.78%, and intracranial hemor- the initial resistance to thrombolytic agents
rhage occurred in 0.57% of patients. The that is often seen. Platelets release throm-
authors reported that there was no obvi- boxane A,, which causes local vasocon-
ous increased risk associated with the 50- striction of the artery, and PAI-1, which
mg dose compared with lower doses of antagonizes the action of thrombolytic
tenecteplase, provided the use of the 50- drugs and contributes to rethrombosis and
mg dose was based on weight (weight- reocclusion. In addition, thrombolytic
based dose, 0.5-0.6 mg/kg). In the weight- drugs directly activate platelets, resulting
adjusted approach, 50 mg is recommended in increased levels of tbromboxane A, and
for patients whose body weight is 290 kg. platelet-activating factor. Moreover, lysis
of clot-bound fibrin exposes additional
bound thrombin to the circulation, which
DRUG INTERACTIONS
can convert fibrinogen to fibrin and lead to
No formal studies of potential interactions rethrombosis.44
between tenecteplase and other drugs have Traditionally, initial therapy for AM1
been performed to date. Because tenecte- has combined an antifibrin agent (eg, a

992
L. DAVYDOV AND J.W.M. CHENG

thrombolytic) with an antithrombin agent low-dose heparin. Eight hundred patients

(eg, unfractionated heparin). Antiplatelet will be recruited. The primary end point
therapy has typically consisted of aspirin. of the dose-finding portion of the trial is
Recently, attention has turned to the po- TIM1 grade 3 flow at 60 minutes, and the
tential role of more potent antiplatelet primary end point of the dose-confirmation
agents such as glycoprotein IIb/IIIa- portion of the trial is ST-segment resolu-
receptor inhibitors. During infarction, a tion at 60 minutes.45
conformational change occurs in the gly- The ENTIRE (Enoxaparin and TNK-
coprotein IIb/IIIa receptor that increases tPA with or Without Glycoprotein IIb/IIIa
fibrinogen binding. Because glycoprotein Inhibitor as Reperfusion Strategy in ST
IIb/IIIa-receptor inhibitors block the final Elevation MI) trial is comparing a stan-
common pathway for platelet aggregation, dard dose of tenecteplase used with ei-
their antiplatelet effects are more potent than ther unfractionated heparin or enoxaparin
those of aspirin or adenosine diphosphate- and a combination regimen of low-dose
receptor antagonists such as ticlopidine tenecteplase/abciximab with low-dose
and clopidogrel.43 enoxaparin or low-dose unfractionated
Several ongoing trials are investigating heparin. The anticipated enrollment is
whether combinations of low-dose throm- -600 patients. The primary end point is
bolytic agents, glycoprotein IIa/IIIb- TIM1 grade 3 flow at 60 minutes, and sec-
receptor inhibitors, standard- or low-dose ondary end points include ST-segment res-
unfractionated heparin, and low-molecular- olution and clinical events.45
weight heparins might have greater effi- The ASSENT-3 study is being con-
cacy and produce a lower rate of bleeding ducted in 6000 patients with AM1 ran-
events than full doses of thrombolytic and domized to 1 of 3 arms: a standard dose of
heparin therapy. Several of these trials are tenecteplase and a reduced dose of hep-
employing tenecteplase as the throm- arin; low-dose tenecteplase, abciximab,
bolytic agent. and a reduced dose of heparin; or a stan-
The INTEGRITI (Integrilin and Tenec- dard dose of tenecteplase with enoxaparin.
teplase in Acute Myocardial Infarction) One thousand patients will be enrolled in
trial is examining the efficacy and tolera- the ASSENT-3 Plus study, which will in-
bility of tenecteplase in combination with vestigate prehospital administration of ei-
unfractionated heparin without eptifi- ther tenecteplase and unfractionated hep-
batide, and 50% to 100% of the standard arin or tenecteplase and enoxaparin.45
tenecteplase dose in combination with ep- It is hoped that the results of these
tifibatide and low-dose heparin. It is an- studies will further define the role of
ticipated that up to 400 patients will be tenecteplase and the appropriate use of
enrolled in this trial. The primary study thrombolytics and other antithrombotic
end point is TIM1 flow at 60 minutes.45 agents in the management of AMI. It is
The FASTER (Fibrinolytic and Aggra- possible that the administration of tenec-
stat ST Elevation Resolution) study is as- teplase as a single bolus may lead to ear-
sessing the efficacy and tolerability of full- lier reperfusion in AM1 and thus may be
dose tenecteplase in combination with useful on a prehospital basis, although
standard-dose heparin and a combination more research into this aspect of tenec-
of low-dose tenecteplase, tirofiban, and teplase use is necessary.

993
 CLINICAL THERAPEUTICS@

CONCLUSIONS thrombolytic strategies for acute myocar-

dial infarction. N Engl J Med. 1993;329:
Tenecteplase is a highly fibrin specific 673-682.

variant of native tPA that has a longer

3. Koren G, Weiss AT, Hasin Y, et al. Pre-
half-life, slower plasma clearance, and in- vention of myocardial damage in acute
creased resistance to inhibition by PAI-1. myocardial ischemia by early treatment
Compared with the complicated regimen with intravenous streptokinase. N Engl J
required to administer the standard fibri- Med. 1985;313:1384-1389.
nolytic alteplase, the pharmacokinetic
properties of tenecteplase allow single- 4. Weaver WD, Cerqueira M, Hallstrom AP,
bolus administration. In clinical trials, et al. Prehospital-initiated vs hospital-
initiated thrombolytic therapy. The Myo-
single-bolus administration of tenecte-
cardial Infarction Triage and Intervention
plase has demonstrated equivalent effi-
Trial. JAMA. 1993;270:1211-1216.
cacy to a 90-minute infusion of alteplase.
The rate of intracranial hemorrhage with 5. Lincoff AM, Top01 EJ. Illusion of reperfu-
tenecteplase was comparable to that with sion. Does anyone achieve optimal reper-
alteplase, but tenecteplase was associated fusion during acute myocardial infarction?
with fewer noncerebral complications and Circularion. 1993;88:1361-1374.
a reduced need for blood transfusions.
6. Tanswell P, Tebbe U, Neuhaus KL, et al.
Whether these differences will result in
Pharmacokinetics and fibrin specificity of
significant cost savings compared with
alteplase during accelerated infusions in
currently used thrombolytic therapies re-
acute myocardial infarction. J Am Co11
mains to be seen, as there have been no Curdiol. 1992:19:1071-1075.
pharmacoeconomic studies of tenecte-
plase to date. 7. Pislaru SV, Van de Werf F. TNK-tPA for
Studies of various combinations often- acute myocardial infarction: The clinical
ecteplase and antithrombotic agents (eg, experience. Thromb Haemost. 1999;82
low-molecular-weight heparin and glyco- (Suppl 1): 117-120.
protein IIb/IIIa-receptor inhibitors) are
8. Van de Werf FJ. The ideal fibrinolytic:
ongoing. The results of these trials will
Can drug design improve clinical results?
further define the role of tenecteplase in Eur Heart J. 1999;20: 1452-1458.
the management of AMI.
9. The Global Use of Strategies to Open Oc-
cluded Coronary Arteries (GUSTO III) In-
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Address correspondence to: Judy W.M. Cheng, PharmD, BCPS, Mount Sinai Medical
Center, Box 1211, One Gustave L. Levy Place, New York, NY 10029. E-mail: Jcheng@
[Link]

997